The present invention relates to synthetic, absorbable monofilament fibers of glycolide-based polymers, especially poly(lactide-co-glycolide) copolymers, that are useful in the fabrication of brachytherapy seed spacers in brachytherapy seed delivery systems.
Prostatic cancer has been estimated to affect as many as one in three men. In the U.S. alone, this implies an estimated fifty-million patients who are candidates for treatment of prostatic cancer. Prior methods of treatment include surgical intervention, external radiotherapy, and other brachytherapy (interstitial radiation) techniques. A general discussion of the localized use of radiation therapy is found in Bagshaw, M. A., Kaplan, I. D. and Cox, R. C., Radiation Therapy for Localized Disease, CANCER 71: 939-952, 1993. Disadvantages associated with surgical intervention include impotence and incontinence. External radiotherapy may have deleterious effects on surrounding normal tissues (e.g., the bladder, the rectum, and the urethra). In contrast, brachytherapy diminishes complications such as impotence and incontinence, and allows a higher and more concentrated radiation dose to be delivered to the prostate gland as compared to external radiotherapy. An additional advantage of brachytherapy is that treatment can be accomplished within a matter of days as compared to weeks, greatly reducing radiation exposure of the adjacent organs.
Prostate brachytherapy can be divided into two categories, based upon the radiation level used. The first category is temporary implantation, which uses high activity sources, and the second category is permanent implantation, which uses lower activity sources. These two techniques are described in Porter, A. T. and Forman, J. D., Prostate Brachytherapy, CANCER 71: 953-958, 1993. The predominant radioactive sources used in prostate brachytherapy include iodine-125, palladium-103, gold-198, ytterbium-169, and iridium-192. Prostate brachytherapy can also be categorized based upon the method by which the radioactive material is introduced into the prostate. For example, an open or closed procedure can be performed via a suprapubic or a perineal retropubic approach.
Prostate cancer is a common cancer for men. While there are various therapies to treat this condition, one of the more successful approaches is to expose the prostate gland to radiation by implanting radioactive seeds. The seeds are implanted in rows and are carefully spaced to match the specific geometry of the patient""s prostate gland and to assure adequate radiation dosages to the tissue. Current techniques to implant these seeds include loading them one at a time into the cannula of a needle-like insertion device, which may be referred to as a brachytherapy needle. Between each seed may be placed a spacer. In this procedure, a separate brachytherapy needle is loaded for each row of seeds to be implanted.
Although seed spacers may be made from a variety of materials, both absorbable and non- absorbable, there are advantages if the material is absorbable. These advantages include minimizing or eliminating any effects due to the long-term presence of the material in the body. Absorbable materials include catgut, collagen, and synthetic absorbable polymers. Catgut and collagen usually degrade by an enzymatic mechanism, as opposed to a chemical mechanism such as reaction with water, that is, hydrolysis. The preferred method of sterilization for brachytherapy seeds and spacers is steam sterilization (autoclaving). When catgut is used as a seed spacer material, the autoclaving process utilized may make the spacer soft, presumably by the plastisizing effects of the water which these materials uptake during exposure. Besides not retaining physical characteristics, catgut seed spacers also can change shape when exposed to autoclaving. Present-day synthetic absorbable materials do not uptake as much water as catgut or collagen. They do, however, degrade by a hydrolysis mechanism. It is well known that these hydrolysis reactions occur at faster rates at higher temperatures. As the preferred sterilization method for brachytherapy seeds and spacers is steam sterilization (autoclaving), it is surprising that synthetic materials known to date can effectively function in these applications. Indeed, based on the knowledge that synthetic absorbable polymers generally degrade by chemical hydrolysis, most would not even consider them for use as medical devices that would be sterilized by autoclaving.
One approach to minimizing the effects of steam sterilization on the premature degradation of seed spacers made from synthetic absorbable polymers would be to consider those synthetic absorbable polymers that are much more resistant to hydrolysis. Such a material is polylactide. This material has a much higher probability of maintaining mechanical properties required for use in brachytherapy seed delivery devices after it has been exposed to autoclaving, compared to, for instance, polyglycolide. Yet, because polylactide takes so much longer to absorb in the body, it is not generally a material of choice. The high-lactide polymer, 95/5 poly(lactide-co-glycolide), used in the production of certain long-term commercial suture materials useful in certain orthopedic surgical procedures, also takes too long to absorb in the brachytherapy procedures.
Other problems exist with certain synthetic absorbable polymers. For instance, the synthetic absorbable polymer poly(p-dioxanone), although known to retain its strength for much longer time periods than polyglycolide, is too low melting to be suitable for sterilization by autoclaving. As such, proper selection of material is an important criterion in the manufacture of monofilament fibers having properties suitable for use as brachytherapy seed spacers.
In addition to material selection, we have found that the process of manufacture is an important factor. Although injection molding appears to be an entirely suitable manufacturing process to make seed spacers, if injection molding most synthetic absorbable polymers is utilized as the manufacturing process, the spacers so produced tend to break down excessively during the sterilization process, retaining very little strength. We have found a process of making brachytherapy seed spacers from glycolide-rich synthetic absorbable polymers entailing a preferred extrusion, drawing, and annealing process to provide monofilament fibers with suitable properties which can be cut to length.
Monofilament fiber, for use in many applications, needs to be particularly straight, devoid of curves or bows, to allow proper functioning. One such application is brachytherapy seed spacers. If the seeds are curved or bowed, they may jam the applier during application of the seed/seed spacer assembly. Additionally, undesirable dimensional spacing variation may result if the seeds are curved initially, or worse yet, curve or bow irreproducibily once in the assembly, as this may initially go undetected. Since the function of brachytherapy seed spacers is to help position radioactive seeds to provide radioactivity in spatially suitable pattern, the seeds must be sufficiently dimensionally accurate and stable. Fibers made by some spinning processes are not straight after extrusion and drawing. They tend to retain some coil memory. Even after rack annealing, fibers made by some processes still can be curved due to residual coil memory.
Other various process conditions may adversely affect the properties required of the fibers for use as brachytherapy seed spacers. Upon sterilization by autoclaving, too much undesirable shrinkage in length may occur or the parts may undergo warping or bending.
Besides the xe2x80x9cbroomingxe2x80x9d that may be experienced upon cutting fibers to length, some fabricated devices, i.e. seed spacers, also may xe2x80x9cbroomxe2x80x9d or split during surgery under mechanical loading. Too much undesirable shrinkage in length, warping or bending upon autoclaving sterilization, or xe2x80x9cbroomingxe2x80x9d or collapse during loading are failures that are particularly troublesome, as they occur at a point when they are difficult to detect or worse yet, during the actual surgical procedure.
It would be advantageous to develop a synthetic, absorbable monofilament fiber that both is absorbable by the body and maintains mechanical properties such that the fibers are suitable for use as brachytherapy seed spacers in brachytherapy seed delivery systems. It also would be advantageous to provide robust processes for reliably making such synthetic absorbable monofilament fibers having absorbability and mechanical strength suitable for use as brachytherapy seed spacers.
According to the present invention, a manufacturing process is provided for the production of a synthetic, absorbable, monofilament fiber suitable for the fabrication of medical devices that require autoclaving as the means of sterilization, such as seed spacers. We have discovered unexpectedly that monofilament fibers prepared from certain glycolide-rich copolymers, which fibers have been oriented in a total draw ratio of 4.1 to 5.9xc3x97, and have been annealed between about 165xc2x0 C. and 185xc2x0 C., can undergo a sterilizing autoclave cycle and still retain sufficient properties so as to allow their use in certain medical procedures, including brachytherapy.
The present invention is directed towards monofilament fibers prepared from polymers containing about 80 to 100 mole percent, preferably about 85 to 100 mole percent, polymerized glycolide monomer. The glycolide homopolymer also is known as polyglycolide or as polyglycolic acid. Preferably the fibers are prepared from polymers comprising 0 to about 15 mole percent polymerized lactide monomer and 100 to about 85 mole percent polymerized glycolide monomer, i.e. poly(lactide-co-glycolide). Most preferably, the polymers comprise about 10 mole percent polymerized lactide monomer and about 90 mole percent polymerized glycolide monomer. The fibers are oriented at a total draw ratio range of 4.1 to 5.9xc3x97, and are annealed at a temperature between about 165xc2x0 C. and about 185xc2x0 C. Such fibers are absorbable by the body and are capable of undergoing an autoclave process used to sterilize brachytherapy seed spacers, while retaining mechanical properties required for use as brachytherapy seed spacers in brachytherapy seed delivery devices. The invention also is directed to brachytherapy seed spacers prepared from the monofilament fibers. The invention also is directed to methods of manufacturing such fibers and brachytherapy seed spacers.
Polymers used in preparation of the monofilament fibers of the present invention must be absorbable by the body when used as brachytherapy seed spacers. By absorbable, it is meant that the material does not simply dissolve away from the implant site, but is converted to lower molecular weight species that are removed from the site and usually from the body by biological means. The conversion to lower molecular weight species, in the case of most synthetic absorbable polymers, is effected by chain cleavage by chemical hydrolysis. In the case of brachytherapy seed spacers, it is preferable to have the devices xe2x80x9cclearedxe2x80x9d in no more than about three or four months after the procedure.
In addition to being absorbable, the fibers prepared from the polymers must possess certain mechanical properties in order to be useful as brachytherapy seed spacers. In particular, the column strength of the fiber, at a minimum, must be effective to prevent the fiber from splitting or brooming upon cutting to length in the manufacture of seed spacers. Preferably, the column strength of the fiber, and subsequently the seed spacer, will be at least 3.5 pounds after autoclaving. The surface of the fiber must be sufficiently smooth for use as brachytherapy seed spacers. In addition, the fiber must be dimensionally stable and autoclaveable, meaning that the fiber retains shape and dimension effective for use as a seed spacer when subjected to an autoclaving process suitable for sterilization of seed spacers and practiced in the hospital environment.
As mentioned earlier, polylactide homopolymers have been found to provide adequate mechanical properties, but are deficient in that they take too long to be absorbed by the body. The melting temperature of poly(p-dioxanone) polymer is too low to survive the autoclave process. The synthetic absorbable polymers containing polymerized glycolide that have glass transition temperatures below room temperature and that have found commercial utility as monofilament sutures, such as the segmented copolymers of glycolide and caprolactone, generally do not have the mechanical properties needed to function as seed spacers after being sterilized by autoclaving. We have thus found that not all synthetic absorbable polymers function equally as seed spacer materials.
It has been unexpectedly discovered that monofilament fibers prepared from glycolide-rich polymers containing about 85 to 100 mole percent polymerized glycolide, preferably made from poly(lactide-co-glycolide), comprising from 0/100 to about 15/85 mole percent lactide/ glycolide, and most preferably, 10/90 poly(lactide-co-glycolide), in which the fibers have been oriented in the total draw ratio range of 4.1 to 5.9xc3x97 and in which the fibers have been annealed at a temperature between about 165xc2x0 to about 185xc2x0 C., may be used to reliably fabricate absorbable, autoclaveable brachytherapy seed spacers for use in brachytherapy seed delivery devices. Despite being absorbable in the body by virtue of a relatively facile reaction rate with water; that is, relatively facile chemical hydrolysis, seed spacers of the subject invention can withstand exposure to water (steam) at the high temperatures, and for the time periods necessary to sterilize by a conventional autoclaving cycle.
Polymers used to prepare fibers according to the present invention generally are prepared from 100 to about 80 mole percent glycolide monomer and from 0 to about 20 mole percent of a copolymerizable comonomer. Exemplary comonomers may be selected from the group consisting of L(xe2x88x92)-lactide, D(+)-lactide, meso-lactide, p-dioxanone, trimethylene carbonate and epsilon-caprolactone. If less than about 80 mole percent glycolide is used, the fibers manufactured therefrom will not possess sufficient mechanical properties required for use in brachytherapy seed spacers. A preferred comonomer is lactide, especially at about a 10 mole percent level. Other sequences may be incorporated in the polymer, for instance, by adding an alpha,omega-dihydroxy compound at the start of the polymerization.
Generally, the polymers of the present invention have molecular weights, prior to extrusion, corresponding to inherent viscosity (IV) values of about 1.0 to about 2.5 dL/g, as measured in hexafluroisopropanol (HFIP) at 25xc2x0 C., at a concentration of 0.1 g/dL. It is preferable that the IV values of the resins range from 1.2 to 2.1 dL/g, more preferably between 1.3 and 2.0 dL/g, and most preferably between 1.4 and 1.7 dL/g. It should be understood that if the molecular weight of the polymer were too low, it would be very difficult to orient the fiber in the draw ratio range required according to the present invention. If the molecular weight is too high, difficulty in conveying the molten resin during extrusion may result.
In a process for making monofilament fibers disclosed in U.S. Pat. No. 4,671,280, entitled Surgical Fastening Device And Method for Manufacture, in the name of Dorband et al., the contents of which are hereby incorporated by reference in their entirety, the fibers prepared from polymers comprising greater than 80 mole percent polymerized glycolide are oriented in a total draw ratio of 7.4xc3x97 and annealed at 135xc2x0 C. On the other hand, fibers according to the present invention must be oriented in a total draw ratio of 4.1 to 5.9xc3x97, more preferably from about 4.5 to about 5.5. When the total draw ratio is too low, the fibers exhibit insufficient column strength retention after autoclaving when used as a brachytherapy seed spacer. When the total draw ratio is too high, the surface of the resulting fiber may be too rough for use as a seed spacer, and/or the ends of the fibers may easily split apart, or xe2x80x9cbroomxe2x80x9d, upon cutting to length or during mechanical loading as occurs during introduction of a seed/seed spacer assembly in surgery.
In order for the process used to manufacture fibers according to the present invention to be robust, it should consistently provide fiber having the mechanical properties required for use in brachytherapy seed spacers, particularly dimensional stability and surface smoothness. We surprisingly have discovered that when the extruded, oriented monofilament fibers comprising 100 to about 80 mole percent polymerized glycolide are oriented to a total draw ratio between 4.1 to 5.9xc3x97 and annealed at a temperature between about 165xc2x0 C. and about 185xc2x0 C., fibers that exhibit required dimensional stability and surface smoothness consistently are provided. When the annealing temperature is less than about 165xc2x0 C., e.g. about 155xc2x0 C., the fibers often exhibit insufficient mechanical properties such as bowing. More preferably, the fibers are annealed between about 170xc2x0 C. and about 180xc2x0 C. Even more preferably, the fibers are annealed at about 175xc2x0 C.
Upon sterilization by autoclaving, too much undesirable shrinkage in length may occur, or parts may undergo warping or bending. Besides the xe2x80x9cbroomingxe2x80x9d that may be experienced upon cutting fibers to length, some fabricated devices, i.e. seed spacers, also may xe2x80x9cbroomxe2x80x9d or split during surgery under mechanical loading. Fibers and spacers that exhibit too much undesirable shrinkage in length, warping or bending upon autoclaving sterilization, or xe2x80x9cbroomingxe2x80x9d, or collapse during loading are considered ineffective for use in brachtherapy.
By xe2x80x9cautoclaveablexe2x80x9d, it is meant that the fiber, in the form of a seed spacer, maintains at least 3.5 lbs of column strength and does not warp or bend during the autoclave cycle, thus preventing its use as a brachytherapy seed spacer.
Although seed spacer diameters between about 30 and 40 mils are particularly advantageous, it is to be understood that the diameter of monofilament fibers of the subject invention can be as low as about 20 mils and as high as about 60 mils or greater. Generally the cross-section of the fibers will be circular, but other shapes may be used to advantage. In the case of non-circular cross-sections, corresponding cross-sectional areas will dominate.
Processes for making the glycolide-rich fibers and brachytherapy seed spacers of the present invention are set forth herein.